Identification of a locus near ULK1 associated with progression-free survival in ovarian cancer

Quinn MC, McCue K, Shi W, Johnatty SE, Beesley J, Civitarese A, O'Mara TA, Glubb DM, Tyrer JP, Armasu SM, Ong JS, Gharahkhani P, Lu Y, Gao B, Patch AM, Fasching PA, Beckmann M, Lambrechts D, Vergote I, Velez Edwards DR, Beeghly-Fadiel A, Benitez J, Garcia MJ, Goodman MT, Dörk T, Dürst M, Modugno F, Moysich K, Du Bois A, Pfisterer J, Bauman K, Karlan BY, Lester J, Cunningham JM, Larson MC, McCauley BM, Kjaer SK, Jensen A, Hogdall CK, Hogdall E, Schildkraut JM, Riggan MJ, Berchuck A, Cramer DW, Terry KL, Bjorge L, Webb PM, Friedlander M, Pejovic T, Moffitt M, Glasspool R, May T, Ene GE, Huntsman DG, Woo M, Carney ME, Hinsley S, Heitz F, Fereday S, Kennedy CJ, Edwards SL, Winham SJ, DeFazio A, Pharoah PD, Goode EL, MacGregor S, Chenevix-Trench G (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Book Volume: 30

Pages Range: 1669-1680

Journal Issue: 9

DOI: 10.1158/1055-9965.EPI-20-1817

Abstract

Background: Many loci have been found to be associated with risk of epithelial ovarian cancer (EOC). However, although there is considerable variation in progression-free survival (PFS), no loci have been found to be associated with outcome at genome-wide levels of significance. Methods: We carried out a genome-wide association study (GWAS) of PFS in 2, 352 women with EOC who had undergone cytoreductive surgery and standard carboplatin/paclitaxel chemotherapy. Results: We found seven SNPs at 12q24.33 associated with PFS (P < 5 × 10-8), the top SNP being rs10794418 (HR = 1.24; 95% CI, 1.15-1.34; P = 1.47 × 10-8). High expression of a nearby gene, ULK1, is associated with shorter PFS in EOC, and with poor prognosis in other cancers. SNP rs10794418 is also associated with expression of ULK1 in ovarian tumors, with the allele associated with shorter PFS being associated with higher expression, and chromatin interactions were detected between the ULK1 promoter and associated SNPs in serous and endometrioid EOC cell lines. ULK1 knockout ovarian cancer cell lines showed significantly increased sensitivity to carboplatin in vitro. Conclusions: The locus at 12q24.33 represents one of the first genome-wide significant loci for survival for any cancer. ULK1 is a plausible candidate for the target of this association. Impact: This finding provides insight into genetic markers associated with EOC outcome and potential treatment options.

Authors with CRIS profile

Involved external institutions

QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) Princess Margaret Cancer Centre / Princess Margaret Hospital Canada (CA) University of British Columbia Canada (CA) BC Cancer Research Centre Canada (CA) University of Cambridge United Kingdom (GB) University of Glasgow United Kingdom (GB) Mayo Clinic United States (USA) (US) Kliniken Essen-Mitte Germany (DE) Peter MacCallum Cancer Centre Australia (AU) Westmead Institute for Medical Research Australia (AU) Westmead Hospital Australia (AU) University of California Los Angeles (UCLA) United States (USA) (US) Flanders Institute for Biotechnology / Vlaams Instituut voor Biotechnologie (VIB) Belgium (BE) University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven Belgium (BE) Vanderbilt University United States (USA) (US) Vanderbilt University Medical Center United States (USA) (US) Spanish National Cancer Research Centre / Centro Nacional de Investigaciones Oncológicas (CNIO) Spain (ES) Cedars-Sinai Medical Center United States (USA) (US) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) Universitätsklinikum Jena Germany (DE) University of Pittsburgh United States (USA) (US) Roswell Park Cancer Institute United States (USA) (US) Philipps-Universität Marburg Germany (DE) University of Copenhagen Denmark (DK) Kræftens Bekæmpelse Denmark (DK) Emory University United States (USA) (US) Duke University Medical Center United States (USA) (US) Harvard University United States (USA) (US) Haukeland University Hospital / Haukeland universitetssykehus Norway (NO) University of New South Wales (UNSW) Australia (AU) Oregon Health and Science University (OSHU) United States (USA) (US) University of Hawaii (U.H.) United States (USA) (US)

How to cite

APA:

Quinn, M.C., McCue, K., Shi, W., Johnatty, S.E., Beesley, J., Civitarese, A.,... Chenevix-Trench, G. (2021). Identification of a locus near ULK1 associated with progression-free survival in ovarian cancer. Cancer Epidemiology Biomarkers & Prevention, 30(9), 1669-1680. https://doi.org/10.1158/1055-9965.EPI-20-1817

MLA:

Quinn, Michael C.J., et al. "Identification of a locus near ULK1 associated with progression-free survival in ovarian cancer." Cancer Epidemiology Biomarkers & Prevention 30.9 (2021): 1669-1680.

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